update for the practicing pathologist: the international

Update for the practicing pathologist: The International Consultation On Urologic Disease-European association of urology consultation on bladder cancer

Mahul B Amin1,27, Steven C Smith1,27,28, Victor E Reuter2, Jonathan I Epstein3, David J Grignon4, Donna E Hansel5, Oscar Lin2, Jesse K McKenney6, Rodolfo Montironi7, Gladell P Paner8, Hikmat A Al-Ahmadie2, Ferran Algaba9, Syed Ali3, Isabel Alvarado-Cabrero10, Lukas Bubendorf11, Liang Cheng4, John C Cheville12, Glen Kristiansen13, Richard J Cote14, Brett Delahunt15, John N Eble4, Elizabeth M Genega16, Christian Gulmann17, Arndt Hartmann18, Cord Langner19, Antonio Lopez-Beltran20, Cristina Magi-Galluzzi6, Jorda Merce14, George J Netto3, Esther Oliva21, Priya Rao22, Jae Y Ro23, John R Srigley24, Satish K Tickoo2, Toyonori Tsuzuki25, Saleem A Umar14, Theo Van der Kwast26, Robert H Young21, and Mark S Soloway14

1Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA 2Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 3Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA 4Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA 5Department of Pathology, University of California San Diego, San Diego, CA, USA 6Department of Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA 7Section of Pathological Anatomy, Polytechnic University of Medicine, United Hospitals, Ancona, Italy 8Department of Pathology, University of Chicago, Chicago, IL, USA 9Pathology Section, Fundacio Puigvert, Universitat Autónoma de Barcelona, Barcelona, Spain 10Department of Pathology, Mexican Oncology Hospital, Mexico City, Mexico 11Institute of Pathology, University Hospital Basel, Basel, Switzerland 12Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA 13Institute of Pathology, University Hospital Bonn, Bonn, Germany 14Department of Pathology, University of Miami Miller School of Medicine, Miami, FL, USA 15Department of Pathology, Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand 16Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, MA, USA 17Department of Pathology, Beaumont Hospital, Dublin, Ireland 18Institute of Pathology, University Erlangen-Nürnberg, Erlangen, Germany 19Institute of Pathology, Medical University Graz, Graz, Austria 20Unit of Anatomical Pathology, Cordoba University Medical School, Faculty of Medicine, Cordoba, Spain 21James Homer Wright Pathology Laboratories, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 22Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA 23Department of Pathology

Correspondence: Dr MB Amin, MD, Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, S. Tower, Rm 8707, Los Angeles, CA 90048, USA. [email protected] authors.28Current address: Department of Pathology, VCU Health System, Richmond, VA 23298, USA.

Disclosure/conflict of interestThe authors declare no conflict of interest.

HHS Public AccessAuthor manuscriptMod Pathol. Author manuscript; available in PMC 2016 September 02.

Published in final edited form as:Mod Pathol. 2015 May ; 28(5): 612–630. doi:10.1038/modpathol.2014.158.

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and Genomic Medicine, The Methodist Hospital Physician Organization, Weill Cornell Medical College of Cornell University, Houston, TX, USA 24Department Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada 25Department of Pathology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan 26Department of Urology, University of Miami Miller School of Medicine, Miami, FL, USA

Abstract

The International Consultations on Urological Diseases are international consensus meetings,

supported by the World Health Organization and the Union Internationale Contre le Cancer, which

have occurred since 1981. Each consultation has the goal of convening experts to review data and

provide evidence-based recommendations to improve practice. In 2012, the selected subject was

bladder cancer, a disease which remains a major public health problem with little improvement in

many years. The proceedings of the 2nd International Consultation on Bladder Cancer, which

included a ‘Pathology of Bladder Cancer Work Group,’ have recently been published; herein, we

provide a summary of developments and consensus relevant to the practicing pathologist.

Although the published proceedings have tackled a comprehensive set of issues regarding the

pathology of bladder cancer, this update summarizes the recommendations regarding selected

issues for the practicing pathologist. These include guidelines for classification and grading of

urothelial neoplasia, with particular emphasis on the approach to inverted lesions, the handling of

incipient papillary lesions frequently seen during surveillance of bladder cancer patients,

descriptions of newer variants, and terminology for urine cytology reporting.

The International Consultation on Urological Diseases (ICUD) is a World Health

Organization (WHO)-registered non-governmental organization promoting improvements in

world health through sponsorship and organization of interdisciplinary international

consultations on the diagnosis, classification, and management of urologic diseases, with

emphasis on provision of evidence-based recommendations. Prior consultations have

spanned the spectrum of neoplastic and non-neoplastic urologic diseases ranging from

benign prostatic hyperplasia and erectile dysfunction to prostate and bladder cancer. Bladder

cancer was previously addressed in 2004 in the 1st International Consultation on Bladder

Tumors in Hawaii with proceedings published in 2005.1 In March 2011 in Vienna, Austria,

bladder cancer was revisited in the 2nd International Consultation on Bladder Cancer to

provide an updated consensus and recommendations. This meeting, co-sponsored by the

European Association of Urology, included a Pathology of Bladder Cancer Work Group

composed of nearly 40 experts in urological pathology among a total of 10 committees

formulated to address key clinical and public health questions. The 2nd Consultation on

Bladder Cancer resulted in recent publication of the book, Bladder Cancer,2 reporting the

consultation’s proceedings, as well as a number of summary papers.3–7 From the standpoint

of bladder cancer pathology, this consultation, auspiciously occurring a number of years

after the discussion in 1997–1998, introduction,8 modification,9 and formal WHO adoption

in 200410 of the International Society of Urologic Pathology (ISUP) classification and

grading system for urothelial neoplasms of the urinary bladder, offered the opportunity to

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examine the state of the art and begin to address a number of key questions regarding

bladder cancer pathology and the pathologist’s diagnostic approach.

As new findings and better data have become available about important areas of recurrent

interest since the 2004 Blue Book, the proceedings of this bladder cancer pathology

committee and working group provide guidance on a number of areas of value to practicing

pathologists. The consultation’s proceedings are publicly available in toto in electronic and

print form2 and provide a compendium of the state of the art for this disease; the pathology

section proceedings alone number >100 pages with >700 references. In particular, sections

describing the microanatomy of the bladder and normal, reactive, and metaplastic epithelial

changes provide a useful review, as does the review of the use of immunohistochemistry.

However, as these proceedings have seen relatively limited coverage in the mainstream

pathology literature, herein we have endeavored to distill a ‘high yield’ review of selected

topics of the proceedings most relevant to the practice of urologic surgical pathology.

Specifically, we cover four areas of the ICUD’s recommendations: (i) the classification and

grading of urothelial neoplasia with a focus on application of the grading system in routine

practice, including for neoplasms with inverted morphology or those with grade

heterogeneity; (ii) the diagnostic approach for incipient lesions, often seen in patients under

surveillance for urothelial neoplasia, which are not accurately classifiable as per the current

schema; (iii) an update on the variants of urothelial carcinoma, particularly from the

perspective of newer variants or established variants with increased understanding of clinical

significance; and (iv) a consensus language for urine cytology. These key offerings of the

ICUD proceedings are bulleted in Summary Box 1.

A historical perspective of classification and grading

Building on the longstanding efforts of the WHO in study and classification of tumors

(reviewed in Mostofi et al9) and the first and second series of the Armed Forces Institute of

Pathology (AFIP) Fascicles,11 the WHO in 1973 published the first international, systematic

approach to the grading of urothelial neoplasia.12 The WHO 1973 system provided a

classification of what was then called ‘transitional cell carcinoma’ of the bladder into three

grades. Although this classification provided the modern foundation for approaching these

lesions, it suffered limitations, particularly pertaining to a lack of clearly defined criteria for

each grade, referring only to the degree of anaplasia and thereby resulting in diagnosis of a

high prevalence of grade II ‘intermediate grade’ carcinomas. A number of authors have

argued that from a clinical standpoint, the 1973 system was limited by focusing on

morphology (without clear criteria) rather than targeted to classifying tumors into categories

more relevant to management.13–15

In 1994, based largely on a study by Jordan et al,16 the 3rd Series AFIP fascicle proposed a

classification of bladder carcinoma as ‘papilloma,’ lowgrade, and high-grade transitional cell

carcinoma,17 adapting a broader definition of ‘papilloma’ to include most WHO 1973 Grade

I transitional cell carcinomas. In fall 1997, anticipatory of the next WHO monograph, to be

published in 1999, Dr FK Mostofi assembled a team of experts at the AFIP in Washington

DC to discuss terminology used in bladder cancer and make recommendations to the WHO.

Of particular interest was the issue of the nomenclature of Grade I transitional cell

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carcinoma, given the growing appreciation at the time that a majority of tumors in this

category did not progress.16,17 At the AFIP meeting, the term papillary urothelial neoplasm

of low malignant potential (PUNLMP) was proposed to the WHO committee, to prevent

assigning these more indolent lesions the label of carcinoma but not categorically

designating them as a benign lesion (papilloma) because of the presence of a distinct subset

of cases that show recurrence and grade progression.

Pursuant to this important step, in March 1998, a follow-up meeting, organized under the

auspices of the International Society of Urologic Pathology (ISUP), was convened at the

United States and Canadian Academy of Pathology (USCAP) meeting in Boston in March,

1998, where the classification, terminology, and, importantly, criteria were refined and

modified (drawing significantly from influential approaches that had been reported by

Malmstroöm et al18 and Murphy et al17). The proceedings of this meeting were published as

the WHO/ISUP Consensus Classification of Urothelial Neoplasms of the bladder at the end

of that year8 in hopes of providing a ‘universally acceptable classification system’ for

urothelial neoplasia. Additional contributions included the formal endorsement of the term

‘urothelial’ to replace ‘transitional cell’ in description of the epithelium of the urinary tract

and tumors therefrom. The flat intraepithelial lesions with non-reactive atypia were

essentially compressed from a multi-tier system of mild, moderate, severe, and carcinoma in

situ (CIS), to essentially a two tier system of dysplasia and CIS. In 1999, the WHO,

maintaining papilloma and PUNLMP as diagnostic categories, re-appropriated the labels of

Grade I, Grade II, and Grade III urothelial carcinoma,9 but used them to label lesions

defined by criteria different from those of the 1973 WHO system.

Subsequently, after a conference in Lyon, France, during 14–18 December 2002, the WHO,

in its revised 2004 ‘Blue Book,’ Pathology and Genetics of Tumours of the Urinary System,

formally adopted the 1998 ISUP system, with its four categories of papilloma, PUNLMP,

low-grade, and high-grade papillary urothelial carcinoma (the latter with option to comment

on diffuse anaplasia if present). This system has been termed the WHO (2004)/ISUP system,

herein the ‘WHO/ISUP System,’ and has provided a number of advantages to the field of

bladder cancer pathology (Summary Box 2). It is this system that the ICUD recommends for

contemporary use, consistent with the endorsement by the 4th Series Armed Forces

Institutes of Pathology Fascicle on the Urinary Bladder,19 the 7th edition AJCC Cancer

Staging Manual,20 and several American (Association of Directors of Anatomic and

Surgical Pathology, the College of American Pathologists21), and European protocols.22 Two

additional areas relevant to grading where the ICUD made recommendations applicable to

daily practice include the application of the WHO/ISUP system to tumors with inverted

architecture and the approach to the diagnosis and reporting of incipient urothelial neoplasia.

Overall ICUD recommendation: grading by WHO/ISUP system

A System Linking Histopathologic Criteria to Risk

The ISUP 1998 consensus classification, adopted by the WHO in 2004 as the WHO/ISUP

system, stressed the use of diagnostic criteria for papillary lesions summarized briefly as

follows. Urothelial papilloma was defined as a papillary lesion showing a urothelium of

normal thickness, cellularity and polarization, lining on fibrovascular stalks, a diagnosis

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implying an unequivocally benign lesion of low risk of recurrence and no risk for

progression. Essentially similar features, seen in flat, nonpapillary mucosa, would be

regarded as normal urothelium. The PUNLMP category of lesions was defined as showing

normal to thickened and hyperplastic-appearing (increased number of layers and cells per

unit area) urothelium with minimal architectural abnormality and minimal cellular atypia.

This group was intended to imply a substantial risk of recurrence (<50%) in some series

approximating that of low-grade papillary carcinoma, but with low risk of progression

(<5%) such that patients could be spared a cancer diagnosis. Lesions showing this range of

features in a nonpapillary lesion or biopsy would be regarded as flat urothelial hyperplasia.

Lesions showing a urothelium with distinct cytologic atypia (nucleomegaly, irregular nuclear

contours, and irregular chromatin distribution) and variable loss of polarity, arrayed on a

discrete fibrovascular core, were defined as low-grade papillary urothelial carcinoma. This

category implies a high risk of recurrence of ~50% and low risk of progression of ~5–10%,

both greater than in PUNLMP. When encountered in a non-papillary lesion, these histologic

changes would be diagnosed as urothelial dysplasia. Finally, tumors demonstrating

urothelium with moderate to severe cytologic atypia (nuclear pleomorphism, prominent

nucleoli, and mitoses, including atypical forms, in mid to higher layers of the urothelium),

arrayed on fibrovascular cores, with variable, often significant loss of polarity and

discohesion, were defined as high-grade papillary urothelial carcinoma. High-grade

papillary carcinomas have relatively greater risk of recurrence than low-grade carcinomas, as

well as a significant risk of progression to invasive disease (15–40%). The same degree of

cytologic atypia, encountered in a biopsy of flat urothelium, would be regarded as urothelial CIS.

ICUD Recommendation—Update for Grading Invasive Carcinoma

One key area where the recommendations of the ICUD differ, indirectly, from the WHO/

ISUP system concerns the approach to histologic grading of invasive lesions. In principle,

the WHO 1973, ISUP 1998, WHO 1999, and WHO(2004)/ISUP systems all recommended

grading invasive carcinoma by the same system under which non-invasive carcinomas are

graded; indeed, the 2004 WHO Blue Book recommends their grading by ‘the degree of

nuclear anaplasia and…architectural abnormalities.’ Emerging understanding in the

intervening years suggests that among tumors showing any extent of invasion of the

basement membrane (pT1 or greater), the histologic grade is both less important

prognostically, as reviewed recently,2,3 as well as nearly operationally irrelevant, given the

overwhelming predominance of high-grade histology (per WHO (2004)/ISUP criteria). For

instance, in a study by Cao et al,23 41/42 tumors showing stromal invasion were graded as

high-grade under the current WHO/ISUP system. Thus, the prevalence of ‘low-grade’ pT1

was too low to evaluate, whereas even application of the 1973 criteria resulted in a non-

significant difference in recurrence-free, progression-free, and overall survival. Similarly, in

a larger cohort, Otto et al24 found that of over 300 pT1 stage tumors, 96% were graded as

high-grade under the WHO/ISUP system, whereas recurrence-free, cancer-free, and overall

survival again did not differ between low- and high-grade (stage pT1 invasive) carcinomas.

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In the end, this finding should not be surprising in that the criteria involved in recognizing

stromal (or muscularis propria) invasion (retraction artifact, single cells, irregularly shaped

clusters, paradoxical inverse maturation) essentially by definition exclude retention of the

architectural features necessary for a low-grade designation (preservation of a modicum of

polarity within the urothelium). Even tumors at the lower end of the spectrum of cytologic

atypia in invasive tumors, the so-called ‘deceptively bland’ variants (nested etc), once

muscle invasive show overall prognoses similar to stage-matched tumors with conventional

morphology.

Thus, based on the growing experience and understanding of criteria subsequent to the

introduction of the WHO (2004)/ISUP system, the ICUD recommends that invasive

urothelial carcinomas, independent of the degree of invasion, be generally graded as high-

grade. This recommendation comes with the understanding that there are uncommon

variants of invasive urothelial carcinoma that may demonstrate idiosyncratic low-grade

cytologic features (including the small and large nested variants—see below) and which

require careful consideration and communication with clinical colleagues. Additionally, this

ICUD recommendation comes with the consideration voiced by some panelists, especially

European colleagues, that a number of protocols and institutional standard practices ascribe

grades to invasive carcinomas using criteria from prior grading systems—principally WHO

1973 defined solely on degree of ‘anaplasia.’12 Thus, while recognizing that, in any case,

stage trumps grade, grading of invasive urothelial carcinoma may be resorted to in very

select situations based on existing institutional or clinical protocols.

ICUD Recommendation—Update for Grading Inverted Neoplasms

One of the themes in the approach to grading urothelial neoplasms in general, considered at

length in the deliberations of the ICUD, was the analogy between morphologic features of

papillary and flat lesions (Table 1). For instance, beginning with the descriptions and criteria

first proposed in the 1998 ISUP Consensus Classification, there was an appreciation that

similar degrees of cytologic changes were appreciable between flat and papillary non-

invasive lesions, such that normal urothelium and papilloma were analogous, flat urothelial

hyperplasia and PUNLMP were analogous, dysplasia and low-grade papillary urothelial

carcinoma were analogous, and urothelial CIS and high-grade papillary urothelial carcinoma

were analogous. Although the 1998 ISUP included a definition of inverted papilloma and

referenced a contemporary report of urothelial neoplasms with inverted or endophytic

architecture,25 it did not address the applicability of the grading system to inverted

neoplasms. For that matter, the WHO (2004) /ISUP system,10 despite recognizing the

existence of inverted papilloma, did not address grading any other inverted lesions and only

considered the issue that inverted/endophytic growth patterns may simulate invasion.25,26

Inverted neoplasms have been the source of some difficulty in urological pathology, as

already recognized in the 1998 WHO/ISUP Consensus.8 In ICUD deliberations, it became

apparent that a formal approach for grading neoplasms showing an inverted growth pattern,

particularly those demonstrating predominant or exclusive inverted growth,27 was not

available under the existing grading systems. The ICUD proceedings note that this

deficiency has resulted in these neoplasms, especially ones with features of PUNLMP but

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with inverted growth, being reported under a number of terminologies.25,26,28–30 Thus, a

recommendation was made to appropriate the existing WHO/ISUP system criteria and

analogy between flat and exophytic papillary neoplasms to inverted/endophytic papillary

lesions.

Although data to support the validity of the application of the WHO/ISUP System of

histologic grading to inverted neoplasms, particularly PUNLMP,31,32 have only begun to

accumulate, the ICUD recommends use of the criteria of the WHO/ISUP system to grade

inverted lesions, which include inverted papilloma (Figure 1a and b), inverted PUNLMP (Figure 1c and d), inverted papillary urothelial carcinoma, low-grade (Figure 2a and b), and

inverted papillary urothelial carcinoma, high-grade (Figure 2c and d, which may be invasive

or noninvasive); see Table 1. Though the ICUD noted that the limited understanding of the

prospective significance of such diagnoses should be recognized and conveyed to clinicians,

the use of standardized criteria and terminology will enable the future studies necessary to

better understand these neoplasms going forward. For that matter, in clinical practice, it is

not uncommon to see tumors with both exophytic/papillary and endophytic/inverted growth;

it is only when the inverted pattern is prominent or predominant that this proposed

terminology should be used.

ICUD Recommendation: Update for Grading Papillary Neoplasia with Grade Heterogeneity

Heterogeneity in the grade of urothelial neoplasms is not infrequent, with some studies

reporting as much as ~40%.33–36 Under the current (and ICUD recommended) WHO/ISUP

system, the recommendation was made to render a grade based on the highest grade area

identified in the tumor.10 The ICUD workgroup acknowledged that some studies have

promulgated ignoring less than 5% of a higher grade neoplasm,34,36 though it did not

endorse this approach. Additionally, the proceedings reviewed the results of studies that have

identified significant differences between the prognosis of non-invasive papillary carcinomas

with predominant high-grade histology and carcinomas with admixed low-grade

components.33,35,36 Overall, the proceedings acknowledged that prospective studies of grade

heterogeneity, approaches to its reporting, and the relationship of these parameters to

outcomes are needed.

Heterogeneity in lesions that show morphology varying between PUNLMP and papillary

urothelial carcinoma, low-grade, pose a less critical clinical distinction given their relatively

similar recurrence rates. In contrast, the implications of mixed low-grade and high-grade

morphology are more clinically important, though both PUNLMP/low-grade and low-grade/

high-grade mixed patterns are encountered.36 More importantly, one of the documented

reasons behind the interobserver variability in the diagnosis of high-grade papillary

carcinoma is that a focus of higher grade histology may be counted as sufficient for

diagnosis by one observer but not another.15 To provide a more complete diagnostic

description of such a process, the ICUD noted that some authors use terminology such as,

‘high-grade papillary urothelial carcinoma arising in a background of low-grade papillary urothelial carcinoma.’

Because the distinction of low-grade and high-grade tumors is clinically significant, the

ICUD recommends that when assigning a grade to a borderline lesion (between low- and

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high-grade), a number of additional factors, including historical data (grade of prior

urothelial neoplasia, frequency of recurrence), as well as salient clinical (size, focality/

multifocality) and pathologic (concurrent CIS, urine cytology results) observations may be

considered. The ICUD recommends consideration of the presence or absence of such factors

as part of the pathologist’s decision whether or not to ‘upgrade’ a borderline lesion to a

higher grade, which is reasonable in light of the ICUD noting that urologists often approach

management of a case based on such factors. In reviewing cases with ‘cusp’ patterns, it is

important to make the assessment on thin, well stained H&E sections, and judicious ordering

of recuts may be helpful in such cases. Finally, the sharing of difficult or borderline cases

with colleagues is strongly recommended, especially as there are no reliable

immunohistochemical or molecular markers that may be recommended, at present, as

validated adjuncts to help make this important determination. A number of experts have

raised concerns regarding increased tendency of practicing pathologists to grade noninvasive

lesions as high-grade; future efforts such as the upcoming new edition of the WHO ‘Blue

Book’ will likely focus on tightening diagnostic criteria.

ICUD recommendation: approach and terminology for incipient lesions

encountered during surveillance

A recurring difficulty concerns what terminology to use in cases of incipient lesions or

‘formes frustes’ of papillary urothelial neoplasia that present in the form of generally small,

proliferative, and hyperplastic lesions as are encountered with some frequency in patients

under endoscopic surveillance for urothelial neoplasia.37 For instance, papillary urothelial hyperplasia, described as lesions showing a urothelium with increased thickness or cell

density and an undulated or ‘tented’ border (importantly, lacking fibrovascular cores or

cytologic atypia) were described,38 confirmed as a clonal process39 and formally adopted as

a diagnostic category in the 1998 WHO/ISUP Consensus.8 In the 2004 WHO ‘Blue Book,’

papillary urothelial hyperplasia was not specifically identified as a distinct category, but

mentioned as a morphologic variation in the spectrum of hyperplasia.10 The ICUD

Consultation endorsed this entity and term.2,3 However, it bears consideration that the

definition of papillary hyperplasia excludes lesions with cytologic atypia, raising the

question of how to diagnostically approach lesions with low- or high-grade cytologic atypia

or even abortive or rudimentary fibrovascular core formation, such as those sampled during

surveillance.

A number of reports have described similar changes in urothelial neoplasia induced by

intravesical therapies, termed as ‘truncated papillae of treated papillary carcinoma’40 or as

‘atypical papillary urothelial hyperplasia.’41 Such changes may be induced by the local

abrasive effect of intravesical agents.40 Under increased clinical scrutiny and sampling of

patients following contemporary protocols, such lesions pose a challenge to the practicing

pathologist regarding diagnostic approach and terminology. Unfortunately, there is no

molecular or immunohistochemical biomarker that may be recommended at this time to help

sort out any given case definitively. Thus, based on the experience of the bladder pathology

workgroup members, the ICUD recommends a general approach to apply when such lesions

are encountered rather than a particular terminology.

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First, the consultation recommends the use of strict criteria for diagnosis of flat urothelial

hyperplasia as opposed to focal or incipient papillary urothelial neoplasia, in particular,

requiring the complete lack of true fibrovascular cores to render a straightforward diagnosis

of flat hyperplasia. Thin fibrovascular cores are a hallmark of urothelial neoplasia,17 and

their presence, even in rudimentary form, in a biopsy under surveillance, is worrisome for

neoplastic persistence or recurrence. Second, reflective of the desire to employ standardized

criteria, the ICUD recommends use of the criteria and terminology of the WHO/ISUP

system to describe the degree of atypia of the proliferative or hyperplastic flat urothelium

such that cases be described in terms of dysplasia or CIS, based on the degree of the

cytologic atypia of the urothelium.

Perhaps most importantly, correlation with the clinical setting, particularly the cystoscopic

impression, is essential to determine whether such a forme fruste lesion was thought to be a

papillary lesion. For instance, in the appropriate clinical scenario, which might include a

prior non-invasive low-grade papillary urothelial carcinoma diagnosis and a clinically

exophytic lesion identified, a patch of hyperplastic urothelium with distinct but mild

cytologic atypia and mild-to-moderate loss of polarity, with only focally to poorly formed

fibrovascular cores may be interpreted as a small low-grade papillary urothelial carcinoma.

However, in the absence of histologic documentation of well-formed exophytic growth and

in the absence of clinical documentation of a papillary lesion, descriptive terminology such

as ‘dysplasia with early papillary formations’ (Figure 3a and b) or ‘CIS with early papillary formations’ to describe low- and high-grade cases (Figure 3c and d), is recommended. The

fact that these terms are descriptive diagnoses needs to be communicated with the treating

urologist, in as much as there are limited data supporting their validity as entities or their

prognostic significance.

ICUD recommendation: update on approach to variants and new patterns

Overall recommendation

The remarkable morphologic plasticity of urothelial carcinoma has been studied in detail,

with numerous patterns of variant morphology and differentiation reported, as reviewed

recently,42,43 and as considered exhaustively by the ICUD proceedings.2 A comprehensive

review of the full range of variants of urothelial carcinoma is beyond the scope of this

review; instead, we provide a focused update regarding variants of urothelial carcinoma that

are not detailed in the 2004 WHO Blue Book,10 including the large nested variant, urothelial

carcinoma with small tubules, urothelial carcinoma with rhabdoid features, and urothelial

carcinoma with chordoid features. Additionally, we provide an update on one key variant,

micropapillary urothelial carcinoma, where new diagnostic, clinical, and molecular data are

available and increasingly relevant to ongoing practice of urologic surgical pathology.

Importantly, the ICUD makes a general recommendation in favor of reporting variant

morphology for urothelial carcinoma, especially as recent studies suggest it may be

underreported in routine practice.44 Reporting of variants will not only inform clinicians but

also enable prospective study and allow correlation with any subsequent recurrence.45

Additionally, similar to the College of American Pathologists reporting approach, in cases

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where multiple variant morphologies coexist, the recommendation is made to report each

variant and the estimated percentage of each variant present.

The Large Nested Variant of Urothelial Carcinoma

The large nested variant of urothelial carcinoma,46 along with the (small) nested variant of

urothelial carcinoma,47 is one of the variants that may present a ‘pseudo benign’

(deceptively bland) appearance. Though the potential of benign proliferations such as von

Brunn’s nests to simulate carcinoma is well known,48 awareness of the large nested variant

is important given that it may simulate a urothelial neoplasm with inverted growth despite

being invasive, often deeply, of the bladder wall. These carcinomas are composed of large

nests of cells that are cytologically bland (see Figure 4a – c). They show a broad, pushing

pattern of invasion, sometimes evocative of the pattern of verrucous carcinomas. In contrast

to the small nested variant, a surface component has been identified with some frequency,

which also often appears low-grade. In the series reported by Cox et al,46 follow-up data

were obtained in 17/23 patients with large nested variant urothelial carcinoma, showing

persistent/progressive disease in 6/17, suggesting that the low-grade appearance is deceptive.

Larger, additional cohorts will be necessary to better understand this variant, its prevalence,

and its prognostic significance;49 however, a number of features have been identified to

assist in its discrimination from potential simulants. First, although these lesions appear low

grade compared with ‘garden variety’ invasive urothelial carcinoma, the degree of atypia is

more in keeping with a low-grade urothelial carcinoma and generally exceeds that of nests

of von Brunn, even in a reactive setting. In the case of small nested carcinoma, the degree of

atypia is usually greater at the deeper aspect of these lesions, somewhat the opposite of that

expected for benign proliferative lesions. Features to consider in support of a large nested

carcinoma include the haphazard and irregular distribution of the nests in the wall of the

bladder (Figure 5a), which is unexpected for embryologic duct remnants (urachal, etc) or

even orifices of duplicated or tangentially sectioned ureteral collecting systems. The

infiltrative appearance of the nests in the wall, especially deep in the muscularis propria,

directly juxtaposed to large caliber bundles of muscularis propria (Figure 5b), is very useful,

because non-invasive inverted urothelial neoplasia should not invade the muscularis propria.

Finally, observation of foci of conventional invasion, apparent in approximately one third of

cases reported previously,46 can be helpful to confirm invasion (Figure 5c).

Urothelial Carcinoma with Small Tubules

Urothelial carcinoma with small tubules50–52 is a rare neoplasm characterized by infiltrative,

small tubules which may be admixed with solid small nests, often showing the low-grade

morphology described in nested cases (Figure 6a – c). The epithelium may be attenuated and

does not show overt glandular or columnar differentiation, and a surface component may not

be present. Given the smaller size of these tubules, generally smaller than that observed in

microcystic urothelial carcinoma,53 this variant may be mistaken for nephrogenic adenoma,

adenocarcinoma of the prostate,54 or even cystitis cystica et glandularis, though generally

these carcinomas show a degree of infiltrative growth, often involving the muscularis

propria, and cytologic atypia, at least focally, exceeding that allowable in nephrogenic

adenoma or other benign lesions in the differential. Also in the differential diagnoses are

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primary adenocarcinomas of the bladder (which generally show more explicit glandular

features, higher grade, variability in acinar size, mucin, and surface/precursor lesions) and

prostatic adenocarcinoma (which may be readily excluded by use of

immunohistochemistry). The importance of this variant remains its recognition and

distinction from benign or malignant processes, as sufficient cases have not yet been studied

to estimate its biologic potential or treatment implications.

Urothelial Carcinoma with Rhabdoid Features

Urothelial carcinoma with rhabdoid features55,56 is another infrequent variant at the

undifferentiated end of the spectrum of urothelial carcinoma. These tumors merit distinction

from malignant extrarenal rhabdoid tumors of soft tissue, which are pathogenetically

unrelated sarcomas generally of the pediatric population,57 with which they share

histomorphologic features. These tumors are rare and often present as a pattern observed in

an otherwise poorly differentiated to undifferentiated urothelial carcinoma. Generally,

carcinomas with rhabdoid features show a friable, discohesive appearance composed of

sheets of cells with characteristic high-grade features, eccentrically located vesicular nuclei

with prominent nucleoli and hyaline cytoplasmic inclusions; identification of a conventional

urothelial component or contemporary urothelialassociated markers58–61 may be helpful

(Figure 7a – c). In the differential diagnosis, one must consider the rare malignant extrarenal

rhabdoid tumors of soft tissue that have been reported in the bladder;62 these tumors do not

express immunohistochemical markers associated with urothelial carcinoma58 and show

prevalent alteration or loss of expression of the gene SMARCB1 (INI1).63

Invasive Urothelial Carcinoma with Chordoid Features

Urothelial carcinoma with chordoid features64 were noted during a retrospective review of

>160 urothelial carcinomas to identify cases with a morphology reminiscent of chordoma,

extraskeletal myxoid chondrosarcoma, myoepithelioma of soft tissue, or yolk sac tumor.

Though at least focal identifiable conventional urothelial carcinoma was seen in all cases, a

striking pattern of cellular cording was present within an abundant myxoid matrix64 (Figure

8a – c). This stromal change, which may be prominent in conventional urothelial carcinoma

and has been described as ‘urothelial carcinoma with prominent myxoid stroma,’65 suggests

that tumors reported as ‘with chordoid features,’ or ‘associated with prominent myxoid

stroma’ are within a similar spectrum of histopathology. Given the lesions in the differential

diagnosis, all these neoplasms show expression of urothelial-associated markers such as p63

and high molecular weight cytokeratin, which may be useful to confirm the diagnosis. In

contrast, markers associated with tumors in the differential, including calponin, glial

fibrillary acidic protein (myoepithelioma), glypican-3 (yolk sac), and brachyury (chordoma)

are negative. Three quarters of the tumors characterized by Cox et al64 showed extension

into perivesical fat or adjacent organs and lymph node metastases. The majority of patients

had persistent disease or died of disease at follow-up.

Micropapillary Urothelial Carcinoma

Though covered in the 2004 WHO Blue Book, recent years have seen several developments

in our understanding of the micropapillary variant of urothelial carcinoma. Although other

variant morphologies have been reported to be associated with aggressive course, especially

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high-stage disease,42 micropapillary urothelial carcinoma remains the variant where the

prognostic implications are more clearly defined and where therapeutic, and, recently,

molecular considerations are most salient. The ICUD noted that there is not a firm criterion

for the proportion of micropapillary histology required to designate a case as micropapillary;

series have studied cases ranging from focal to almost pure micropapillary histology.66,67

There are indications that the extent of micropapillary differentiation is prognostically

significant, with the proportion of micropapillary morphology identified on transurethral

resection shown to predict stage,68 disease-specific survival,66 or both.69 For this reason, the

general ICUD recommendation is to both report this variant morphology and estimate its

proportion (as above).

These carcinomas were originally described as reminiscent of papillary serous

adenocarcinomas of the ovary,70 a differential diagnostic consideration which, along with

micropapillary variant carcinomas of the breast and other sites, remains salient today. The

morphology is described as slender, delicate filiform processes or small clusters of cells,

generally without true fibrovascular cores (hence the ‘micro’), which appear tightly

clustered in lacunar spaces arrayed in an infiltrative growth pattern70 (Figure 9a).

Particularly when this morphology is extensive, lymphovascular invasion is almost

invariably present, showing a similar pattern of clustered micropapillae present within

vascular spaces.71 Proceeding from data that variants of urothelial carcinoma, including

micropapillary, may be under44 or over-recognized in the practice of surgical pathology and

a desire to better characterize its diagnostic features, Sangoi et al72 performed an

interobserver reproducibility study of micropapillary urothelial carcinomas, sharing cases

among a number of experts of the field. Although a number of features were identified as

sensitive markers of micropapillary carcinoma, especially prominent retraction artifact,

which may be seen in conventional urothelial carcinomas that do not meet criteria for the

micropapillary variant (Figure 9b), the features that were identified as most specific to

consensus micropapillary cases studied were the features of ‘multiple nests in the same

lacuna’ (Figure 9c), ‘intracytoplasmic vacuolization,’ and related ‘epithelial ring forms’

(Figure 9d).72 These features will be of use for prospective evaluation of clinical cases.

Lastly, the clinical significance of micropapillary urothelial carcinoma has evolved

substantially in the past few years. Consistent with observations of predominant high-stage

disease, including deep, extensive invasion and positive lymph nodes,66–70 the

recommendation for early cystectomy (rather than trial of intravesical therapy) has been

advocated by some, even when muscle invasion has not been documented.73 However, other

groups have retrospectively reviewed their experience with micropapillary cases and noted

locally advanced disease with nodal metastasis, even in cases without pre-cystectomy

documentation of muscle invasion, suggesting consideration of neoadjuvant chemotherapy.74

In contrast, other groups have questioned the need for aggressive management (by whatever

means) particularly in cases showing a low percentage of micropapillary morphology, lack

of associated CIS, and lack of muscle invasion.68,75 There is far from a consensus regarding

the clinical implications of diagnosis of micropapillary urothelial carcinoma and its most

appropriate management algorithm. This variant should be approached with clear criteria

and documentation of the percentage of micropapillary component (as with other

morphologic variants), emphasis on careful communication with clinicians, and awareness

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that implications may be significant, depending on institutional practices. Most promising

for this disease, going forward, are recent molecular observations, which suggest a high

prevalence of lesions involving ERBB2, the HER2 oncogene, which may be amplified76,77

or mutated,78 providing a therapeutically tractable target. Of note, ERBB2 abnormalities in

urothelial neoplasms are not limited to micropapillary carcinoma. In a recent integrative

analysis of 97 high-grade invasive urothelial carcinomas, none of the five tumors harboring

amplification exhibited any micropapillary histology.79

ICUD recommendation: urine cytology reporting

One final area where the ICUD consultation proceedings impact directly on practice in

pathology concerns urine cytology. We recommend the reader to review the consultation’s

proceedings and related summaries for coverage of its recommendations for the role of

cytology in screening and monitoring bladder cancer patients, as well as for commentary

regarding the role for molecular assays in cytology.2,3 The ICUD recommends a specific

approach and terminology for reporting urine cytology results, which is summarized in

Table 2. This approach, which is modeled after the Papanicolaou Society of Cytopathology

Practice and Guidelines Task Force recommendations, provides a format that mimics the

Bethesda 2001 System for reporting cervical cytology.80 In particular, the recommendations

emphasize inclusion within the diagnostic section of a statement documenting the anatomic

site of origin of the urinary tract specimen (bladder, urethra, ureter, or renal pelvis), as well

as a statement documenting the technique whereby the sample was obtained (voided urine,

washings, brushings, etc). Finally, the recommendation is made to employ a comment

section, which could be used at the discretion of the cytopathologist, to list additional

findings or to clarify any findings listed in the diagnostic categories.

The ICUD proceedings specifically addressed issues regarding several of the recommended

diagnostic terms. In particular, in the group of diagnoses related to epithelial cell

abnormalities, the relationship of the diagnostic categories atypical urothelial cells and low-grade urothelial carcinoma was addressed. The consultation clarified that because of the lack

of specific criteria for identification of low-grade urothelial carcinoma, most such cases

would be included within the atypical urothelial cells group. Additionally, as regards the

atypical urothelial cells diagnostic category, the ICUD acknowledged that there remains a

lack of consensus as to what criteria are appropriate to define inclusion in this category.

Despite this lack of clarity, the consultation noted that recent reports suggest that this

category may be substratified into two classes, implying differential acuity of follow-up.

These two subclasses are atypical urothelial cells of undetermined significance, the

implication being to follow with repeat urine cytology, as compared with atypical urothelial cells, cannot rule out high-grade carcinoma or atypical urothelial cells, favor neoplasm,

which imply the need for endoscopic evaluation.81,82

Subsequent to the published ICUD proceedings, the International Academy of Cytology

(IAC) in its 2013 congress in Paris proposed new consensus guidelines for urologic cytology

samples, which includes reporting urinary cytopathology. These guidelines will be known as

‘The Paris System for Reporting Urinary Cytopathology’ and will be published in 2016.

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Conclusion

The Second International Consultation on Bladder Cancer, conducted nearly 10 years since

the first consultation and the WHO Blue Book update in 200410 represents a body of work

and consensus, developed over a decade, the summary of which is provided here (Summary

Box 1), available online, and in other summaries. We recommend that surgical pathologists

in practice avail themselves not only to the review of the state of the art of bladder cancer

pathology provided in the document, but also to reviews and recommendations regarding

screening and surveillance protocols, molecular biomarkers, stage-specific clinical

guidelines, chemotherapy, and non-urothelial bladder cancers. The entire consultation text is

available as a downloadable document file at no cost, providing a comprehensive textbook of

the disease. Given the ICUD’s stressing evidence-based recommendations, areas where

evidence or consensus is lacking are noted and represent opportunities for future clinical and

translational investigation.

Finally, it bears consideration that the updated WHO ‘Blue Book’ classification of the

pathology of tumors of urinary system and male genital organs, including as it did in 2004 a

classification of tumors of the bladder,10 is rapidly approaching. As deliberations occur and

result in a revised WHO monograph to be widely available within the next 2 years, the

ICUD recommendations can provide an interim update for use in practice and for

consideration for formal adoption.

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75. Spaliviero M, Dalbagni G, Bochner BH, et al. Clinical outcome of patients with T1 micropapillary urothelial carcinoma of the bladder. J Urol. 2014; 192:702–707. [PubMed: 24603101]

76. Ching CB, Amin MB, Tubbs RR, et al. HER2 gene amplification occurs frequently in the micropapillary variant of urothelial carcinoma: analysis by dual-color in situ hybridization. Mod Pathol. 2011; 24:1111–1119. [PubMed: 21516078]

77. Schneider SA, Sukov WR, Frank I, et al. Outcome of patients with micropapillary urothelial carcinoma following radical cystectomy: ERBB2 (HER2) amplification identifies patients with poor outcome. Mod Pathol. 2014; 27:758–764. [PubMed: 24186136]

78. Ross JS, Wang K, Gay LM, et al. A high frequency of activating extracellular domain ERBB2 (HER2) mutation in micropapillary urothelial carcinoma. Clin Cancer Res. 2014; 20:68–75. [PubMed: 24192927]

79. Iyer G, Al-Ahmadie H, Schultz N, et al. Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer. J Clin Oncol. 2013; 31:3133–3140. [PubMed: 23897969]

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Summary Box 1: Key ICUD updates and recommendations

1. The grading system of choice for papillary and flat non-invasive

urothelial neoplasia is the WHO (2004)/ISUP System.

2. Generally, invasive urothelial carcinoma should be graded as high-

grade, irrespective of the depth of invasion. Recognizing that this issue is not completely resolved, invasive tumors may be further graded as required by institutional or clinical trial protocols.

3. The criteria used in the WHO/ISUP System can be extrapolated to

inverted neoplasia, which are classified as inverted papilloma; inverted PUNLMP; inverted urothelial carcinoma, low-grade, non-invasive; inverted urothelial carcinoma, high-grade, non-invasive; inverted urothelial carcinoma, high-grade, invasive.

4. Diagnostic terminology for incipient papillary lesions not accurately

classifiable per the current system seen in patients under surveillance

include dysplasia with early papillary formations and carcinoma in situ with early papillary formations. Correlation with cystoscopic findings

is a prerequisite.

5. Approach for neoplasms with grade heterogeneity:

a. Assign by highest grade component, as per the WHO/

ISUP System.

b. In equivocal cases, consider key clinicopathologic data,

including focality/multifocality, grade of prior

diagnoses, size of lesions, frequency of recurrence,

presence/absence of concurrent CIS, cytologic

impressions; these parameters may help in deciding

whether to ‘upgrade’ an equivocal lesion.

c. There is no established role for immuno-histochemical

or molecular assays in this setting.

6. Variants of urothelial carcinoma not reviewed in the WHO 2004

include:

a. Large nested variant.

b. Urothelial carcinoma with small tubules.

c. Undifferentiated carcinoma with rhabdoid features.

d. Urothelial carcinoma with chordoid features.

7. Micropapillary urothelial carcinoma has received much attention for:

a. Refined criteria for increased diagnostic repro-

ducibility; key features include ‘multiple nests in the

same lacuna’ and ‘epithelial ring forms’

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b. Clinical implications: controversy over role for early

cystectomy.

c. Distinctive molecular features: ERBB2 mutation and

amplification.

8. Recommendation of diagnostic terminology for urine cytology:

a. Document anatomic source/site of specimen in

diagnosis.

b. Document technique used for sampling.

c. Recommended diagnostic terminology—See Table 2.

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Summary Box 2: Major contributions of the WHO (2004)/ISUP System

1. Establishment of uniform terminology, definitions, and criteria for

papillary neoplasia, removing ambiguity of the WHO 1973 system (eg,

transitional cell carcinoma grade I-II, transitional cell carcinoma grade

II-III)

2. Simplification of flat urothelial lesions with non-reactive atypia into

dysplasia and CIS

3. Application of similar overall criteria, by analogy, between papillary

and flat lesions, underpinning of the ICUD recommendation for use in

inverted lesions

4. Creation of a category of tumor that identifies a tumor with a negligible

risk of progression (PUNLMP), whereby patients avoid the label of

carcinoma but are not given ‘benign’ diagnosis obviating follow-up

5. Identification of a clinically high risk group who are candidates for

intravesical management (high-grade papillary urothelial carcinoma,

urothelial CIS)

6. Identification of a larger group of patients, relative to WHO 1973 grade

III, who are at increased risk for invasive disease and merit closer

follow up

7. Overall stratification of bladder tumors into prognostically significant

categories

8. The classification system has been widely accepted by the ICUD,

UICC, AJCC, AFIP Fascicles, and American (CAP, ADASP) and

European protocols.

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Figure 1. Inverted papilloma and inverted papillary urothelial neoplasm of low malignant potential

(PUNLMP). (a) An inverted urothelial papilloma shows endophytic growth of non-

hyperplastic, non-atypical urothelium. (b) Often a suggestion of peripheral palisading is

apparent, while the epithelium may frequently take on a bland, spindled appearance. (c) An

inverted PUNLMP, similar to exophytic PUNLMP is composed of a hyperplastic (increased

cells per unit area and/or increased thickness) urothelium growing in an endophytic pattern.

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(d) By definition, PUNLMP demonstrates no more than mild atypia and rare mitoses within

a urothelium with preserved polarity.

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Figure 2. Inverted papillary urothelial carcinoma, low-grade and high-grade. (a) Papillary urothelial

carcinoma, low-grade, with predominant inverted growth shows a degree of cellularity and

loss of polarity beyond that allowable in a PUNLMP. (b) Distinct, mild to moderate

cytologic atypia is apparent. (c) Papillary urothelial carcinoma, high-grade, with

predominant inverted growth shows even greater loss of order in the epithelium. This

example showed foci of lamina propria invasion (asterisked), more extensive in adjacent

fields, illustrated here to mainly contrast with the predominantly non-invasive component.

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(d) Loss of polarization with respect to the basement membrane is increased, while greater

nuclear atypia is apparent; an atypical mitosis is identified.

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Figure 3. Update on ‘formes frustes’ of papillary neoplasia. (a and b) Two examples of lesions that, if

encountered in a biopsy of a patient under surveillance for papillary urothelial neoplasia,

without a clinical impression of a papillary lesion may be termed ‘urothelial dysplasia with early papillary formations.’ Correlation with cystoscopic impression is key, as a lesion such

as (b) may be diagnosed outright as papillary carcinoma, low-grade if clinically documented

as a tumor. (c and d) Two examples of lesions that, if encountered in a similar scenario

would be termed ‘urothelial carcinoma in situ with early papillary formations’; the lesion in

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(d) is better developed such that it may be considered sufficient to diagnose papillary

urothelial carcinoma, high-grade, particularly if there is any endoscopic suspicion for a

lesion. The ICUD notes that clinicopathologic correlation is essential to use these diagnostic

terms.

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Figure 4. (a) The large nested variant of urothelial carcinoma may be high stage, as illustrated by deep

muscularis propria invasion. (b) Despite the aggressive growth pattern, a well-polarized

epithelium is preserved. (c) Atypia is less than expected for invasive carcinoma and raises

consideration of low-grade inverted neoplasia.

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Figure 5. Difficulties in diagnostic approach to large nested lesions. (a) This example of a muscularis

propria invasive large nested urothelial carcinoma illustrates the diagnostic challenges, given

cautery and crush artifacts and the low-grade appearance. If the lesions were not

multifocally involving the muscularis propria, benign mimics such as urachal remnants or

orifices of duplicated or tangentially sectioned ureters could be considered. (b) In another

large nested case, the haphazard pattern of the nests is helpful in exclusion of benign

anatomic or vestigial structures, as is their direct juxtaposition to large compact muscle

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bundles of muscularis propria (asterisked). Noninvasive inverted neoplasms should not

generally extend into the muscularis propria. (c) Observation of a focus of conventional-type

invasion (bracketed), consisting of irregularly sized and shaped invasive cell clusters, can be

very helpful to exclude a non-invasive inverted neoplasm.

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Figure 6. (a) Urothelial carcinoma with small tubules presents an infiltrative pattern of variably sized

small tubules. (b) The epithelium lining the tubules is frequently attenuated, prompting

consideration of nephrogenic adenoma or other processes. (c) These lesions may be deeply

invasive of muscularis propria despite the low-grade appearance.

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Figure 7. (a) Urothelial carcinoma with rhabdoid features is a pattern on the spectrum of poorly

differentiated to undifferentiated urothelial carcinoma showing ‘rhabdoid’ morphology of

discohe-sive cells with eccentric nuclei with prominent nucleoli and inclusion-like

eosinophilic cytoplasmic inclusions. (b) Identification of a recognizable conventional

urothelial carcinoma is helpful. (c) Expression of the urothelial carcinoma-associated

marker, S100P, was diffuse, as were uroplakin II and GATA3 in this case.

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Figure 8. (a) Urothelial carcinoma with chordoid features shows cords to reticular growth of epithelial

cells in a myxoid stroma evocative of extraskeletal myxoid chondrosarcoma. (b) Another

case shows clustered cells in abundant myxoid stroma. (c) These cases often present with

high stage.

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Figure 9. Update on features of micropapillary urothelial carcinoma. (a) Micropapillary urothelial

carcinoma with invasion of the muscularis propria. (b) Prominent retraction artifact,

apparent in this conventional urothelial carcinoma, may simulate micropapillary carcinoma.

(c) Two specific features of micropapillary urothelial carcinoma illustrated here are ‘multiple

nests in the same lacuna’ and ‘inverse polarization’ of the epithelium with peripherally

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oriented nuclei. (d) ‘Epithelial ring forms,’ asterisked at center, are another highly specific

feature helpful in diagnosis.

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Table 1

Analogy for application of WHO/ISUP system to inverted neoplasia

Degree of atypia Exophytic papillary lesions Flat lesions Endophytic/inverted papillary lesionsa

None Papilloma Normal Inverted papilloma

Minimal PUNLMPb Urothelial hyperplasia Inverted PUNLMPb

Distinct, mild-moderate Papillary urothelial carcinoma,low-grade, non-invasive

Urothelial dysplasia Inverted papillary urothelial carcinoma,low-grade, non-invasive

Moderate-severe Papillary urothelial carcinoma,high-grade, non-invasive

Urothelial CIS Inverted papillary urothelial carcinoma,high-grade, non-invasive

Severe Papillary urothelial carcinoma,high-grade, invasive

Urothelial carcinoma,high-grade, invasive

Inverted papillary urothelial carcinoma,high-grade, invasive

aInverted lesions may show areas with both exophytic and endophytic growth, but should be at least predominantly inverted to be designated as

such.

bPapillary urothelial neoplasm of low malignant potential.


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Table 2

ICUD recommended format and nomenclature for urine cytology

I. Adequacy statement (optional)

Satisfactory for evaluation

List any quality factors affecting specimen

Unsatisfactory for evaluation (give reason)

II. General categorization

Negative for epithelial cell abnormality (see Descriptive diagnoses)

Epithelial cell abnormality present (see Descriptive diagnosis)

III. Descriptive diagnosis

Negative for epithelial cell abnormality

Infectious agents

Bacterial organisms

Fungal organisms

Viral changes (CMV, herpes, adenovirus, polyomavirus)

Nonspecific inflammatory changes

Acute inflammation

Chronic inflammation

Changes consistent with xanthogranulomatous pyelonephritis

Cellular changes associated with:

Chemotherapeutic agents

Radiation

Epithelial Cell Abnormalities

Atypical urothelial cells (*see comment)

Low-grade urothelial carcinoma

High-grade urothelial carcinoma (invasive carcinoma vs carcinoma in situ)

Squamous cell carcinoma

Adenocarcinoma

Other malignant neoplasms (specify type)

IV. Other—Any molecular findings

V. Comment—Use at cytopathologist discretion to report or clarify other findings


update for the practicing pathologist: the international

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